Method of using [1,2,4]triazolo[4,3-a]quinoxaline-4-amine derivatives as antidepressant and antifatigue agents

Abstract

A series of novel [1,2,4]triazolo[4,3-a]quinoxaline-4-amine derivatives wherein the amine group is optionally substituted with lower alkyl, phenylalkyl having up to three carbon atoms in the alkyl moiety or alkanoyl having from two to five carbon atoms, or the amine group alternatively completes a piperazino ring, the quinoxaline ring is optionally substituted with fluorine, chlorine, bromine or methoxy, and the triazolo ring is optionally substituted with lower alkyl, lower perfluoroalkyl or phenyl are disclosed. These novel compounds are useful for treatment of symptoms associated with depression. Also disclosed are pharmaceutical compositions containing the novel compounds of this invention and a method of using the compounds in the treatment of depression and fatigue.

I claim: 
     
       1. A pharmaceutical composition in unit dosage form for use in the treatment of depression and fatigue comprising a pharmaceutically acceptable carrier and an antidepressant/anti-fatigue effective amount of a compound selected from the group consisting of [1,2,4]triazolo[4,3-a]quinoxaline-4-amine bases of the formula: ##STR3## and the pharmaceutically acceptable acid addition salts thereof, wherein X and X 1  are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine and methoxy; R 1  is selected from the group consisting of hydrogen, lower alkyl, lower perfluoroalkyl and phenyl; and   R 2  and R 3  are each selected from the group consisting of hydrogen, lower alkyl, phenylalkyl having up to three carbon atoms in the alkyl moiety and alkanoyl having from two to five carbon atoms, provided that at least one of X, X 1  and R 1  is always other than hydrogen or lower alkyl when each of R 2  and R 3  is hydrogen or lower alkyl; or   R 2  and R 3 , when taken together, complete a piperazino ring.   
     
     
       2. A pharmaceutical composition as claimed in claim 1 wherein X and X 1  are each hydrogen, Rl is trifluoromethyl, and R 2  and R 3  are each hydrogen or lower alkyl. 
     
     
       3. A pharmaceutical composition as claimed in claim 1 wherein X and X 1  are each hydrogen, R 1  is lower alkyl and R 3  is acetyl. 
     
     
       4. A pharmaceutical composition as claimed in claim 3 wherein R 1  is ethyl and R 2  is hydrogen. 
     
     
       5. A pharmaceutical composition as claimed in claim 3 wherein R 1  and R 2  are both ethyl. 
     
     
       6. A pharmaceutical composition as claimed in claim 3 wherein R 1  is ethyl and R 2  is acetyl. 
     
     
       7. A pharmaceutical composition as claimed in claim 1 wherein at least one of X and X 1  is fluorine, R 1  and R 2  are each hydrogen and R is lower alkyl. 
     
     
       8. A pharmaceutical composition as claimed in claim 7 wherein X is fluorine at the 8-position of the molecule and R 3  is isopropyl. 
     
     
       9. A pharmaceutical composition as claimed in claim 7 wherein X is fluorine at the 7-position of the molecule, X 1  is fluorine at the 8-position of the molecule and R 3  is isopropyl. 
     
     
       10. A pharmaceutical composition as claimed in claim 1 wherein at least one of X and X 1  is chlorine, R 1  is lower alkyl or trifluoromethyl, R 2  is hydrogen and R 3  is hydrogen lower alkyl or alkanoyl having two to five carbon atoms. 
     
     
       11. A pharmaceutical composition as claimed in claim 10 wherein X is hydrogen, X 1  is chlorine at the 8-position of the molecule, R 1  is ethyl and R 3  is isopropyl. 
     
     
       12. A pharmaceutical composition as claimed in claim 10 wherein X is hydrogen, X 1  is chlorine at the 8-position of the molecule, R 1  is ethyl and R 3  is propionyl. 
     
     
       13. A pharmaceutical composition as claimed in claim 10 wherein X is hydrogen, X 1  is chlorine at the 8-position of the molecule, R 1  is trifluoromethyl and R 3  is hydrogen 
     
     
       14. A pharmaceutical composition as claimed in claim 10 wherein X is hydrogen, X 1  is chlorine at the 8-position of the molecule, R 1  is trifluoromethyl and R 3  is acetyl. 
     
     
       15. A pharmaceutical composition as claimed in claim 10 wherein X is hydrogen, X 1  is chlorine at the 8-position of the molecule, R 1  is trifluoromethyl and R 3  is isopropyl. 
     
     
       16. A pharmaceutical composition as claimed in claim 10 wherein X is hydrogen, X 1  is chlorine at the 8-position of the molecule, R 1  is ethyl and R 3  is acetyl. 
     
     
       17. A pharmaceutical composition as claimed in claim 10 wherein X is chlorine at the 7-position of the molecule, X 1  is chlorine at the 8-position of the molecule, R 1  is ethyl and R 3  is hydrogen. 
     
     
       18. A pharmaceutical composition as claimed in claim 1 wherein at least one of X and X 1  is fluorine, R 1  is trifluoromethyl, R 2  is hydrogen and R 3  is hydrogen, lower alkyl or alkanoyl having from two the five carbon atoms. 
     
     
       19. A pharmaceutical composition as claimed in claim 18 wherein X is hydrogen, X 1  is fluorine at the 8-position of the molecule and R 3  is hydrogen. 
     
     
       20. A pharmaceutical composition as claimed in claim 18 wherein X is hydrogen, X 1  is fluorine at the 8-position of the molecule and R 3  is isopropyl. 
     
     
       21. A pharmaceutical composition as claimed in claim 18 wherein X is hydrogen, X 1  is fluorine at the 8-position of the molecule and R 3  is acetyl. 
     
     
       22. A pharmaceutical composition in unit dosage form for use in the treatment of depression and fatigue comprising an antidepressant/anti-fatigue effective amount of a compound selected from the group consisting of [1,2,4]triazolo[4,3-a]quinoxaline-4-amine bases of the formula: ##STR4## and the pharmaceutically acceptable acid addition salts thereof, wherein R 1  and R 2  are each hydrogen and R 3  is ethyl or isopropyl; R 1  is hydrogen or methyl, and R 2  and R 3  are each ethyl;   R 1  is ethyl, R 2  is hydrogen and R 3  is hydrogen, methyl or ethyl; and   R 1  is ethyl, and R 2  and R 3  are each methyl or ethyl.   
     
     
       23. A pharmaceutical composition as claimed in claim 22 wherein R 1  and R 2  are each hydrogen and R 3  is ethyl. 
     
     
       24. A pharmaceutical composition as claimed in claim 22 wherein R 1  is ethyl, R 2  is hydrogen and R 3  is ethyl. 
     
     
       25. A pharmaceutical composition as claimed in claim 22 wherein R 1 , R 2  and R 3  are each ethyl.